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Role of Ca2+ availability to myofilaments and their sensitivity to Ca2+ in myocyte contractile dysfunction in heart
S Kinugawa1, H Tsutsui, S Satoh
1Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, Fukuoka, Japan.
Insights
Heart failure (HF) reduces myocyte contractile function primarily due to decreased intracellular calcium availability, not altered myofilament sensitivity. This finding clarifies cellular defects in HF.
Area of Science:
- Cardiology
- Cellular Biology
- Biochemistry
Background:
- Heart failure (HF) is characterized by depressed myocyte contractile function.
- The cellular basis for this dysfunction, whether reduced calcium availability or impaired myofilament sensitivity, remains unclear.
Purpose of the Study:
- To investigate the cellular mechanisms underlying contractile dysfunction in heart failure at the myocyte level.
- To differentiate between decreased intracellular calcium ([Ca2+]i) availability and altered myofilament sensitivity to calcium as causes of depressed contractility in HF.
Main Methods:
- Isolated left ventricular myocytes from dogs with pacing-induced HF were used.
- Cell shortening and [Ca2+]i transients were measured using indo-1 fluorescence.
- Myofilament calcium sensitivity was assessed via shortening-[Ca2+]i relations in intact and skinned myocytes.
Main Results:
- Myocytes from HF dogs exhibited depressed peak cell shortening and reduced [Ca2+]i transient amplitude.
- A strong positive correlation was observed between cell shortening and [Ca2+]i transient amplitude (r = 0.71).
- Myofibrillar sensitivity to Ca2+ was comparable between control and HF myocytes across different sarcomere lengths.
Conclusions:
- The primary cellular defect in myocyte contractile dysfunction in HF is a reduction in calcium availability to the myofilaments.
- Inherent defects in myofilament sensitivity to calcium do not appear to be the cause of contractile dysfunction in this HF model.
Objective:
Contractile function is depressed at the isolated myocyte level in heart failure (HF), which could result from the decreased availability of intracellular calcium ([Ca2+]i) to the myofibrils and/or the depressed sensitivity of myofilaments to [Ca2+]i. However, the cellular basis of contractile dysfunction remains unestablished.
Methods:
We isolated left ventricular myocytes from dogs with rapid pacing-induced HF. Cell shortening and [Ca2+]i transients were measured by indo-1 fluorescence and the myofilament Ca2+ sensitivity was analyzed by the shortening-[Ca2+]i relation in intact myocytes as well as by the pCa tension relation in skinned cells.
Results:
Peak cell shortening magnitude was depressed in HF, associated with a parallel decrease of [Ca2+]i transient amplitude. There was a significant positive correlation between these two variables (r = 0.71, P < 0.01). In contrast, myofibrillar sensitivity to Ca2+, determined by both intact and skinned myocytes, was comparable between control and HF. Further, there was no significant difference in Ca2+ sensitivity between control and HF even at shorter (1.8 microns) or longer (2.2 microns) sarcomere length.
Conclusions:
Using both intact and skinned cellular preparations, a potential defect in myocyte contractile function in HF was a reduction in Ca2+ availability to the myofilaments, rather than the inherent defects in myofilament sensitivity to Ca2+.